tbuckley/cabot-search huggingface dataset:
Abstract 691: Antineoplastic effect of marina crystal minerals (MCM) against the growth of murine mammary adenocarcinoma cells in vivo
Authors: Nariman K. Badr El-Din, Mai Alaa El-Dein, Mamdooh Ghoneum
Journal: Cancer Research (2022)

Abstract Purpose: Marina crystal minerals (MCM) is a crystallized mixture of minerals and trace elements from sea water. Earlier in vitro studies have shown that MCM possesses apoptotic and immune modulatory effects in human breast cancer cells MDA-MB-231. The current study aimed to evaluate the anticancer effect of MCM in vivo against the growth of murine mammary adenocarcinoma cells and to explore the mechanisms underlying its effect. Materials and Methods: Mice were inoculated intramuscularly with Ehrlich ascites carcinoma (EAC) cells, a breast adenocarcinoma of mouse origin. The tumors grew and became palpable within 9 days post-inoculation. Tumor-bearing mice were injected with MCM intraperitoneally (IP) or intratumorally (IT) at a dose of 40 mg/kg BW for 6 days/week. Different parameters were evaluated, including tumor growth, cell cycle progression, cell cycle regulatory proteins, apoptosis, apoptotic regulatory markers, mitochondrial membrane potential (MMP), natural killer (NK) cell activity, and histopathological effects. Results: Treatment with MCM caused a reduction in tumor volume by 49.4% for IP and 59.5% for IT injection. MCM induced apoptosis in cancer cells, as indicated by the appearance of a sub-G1 peak and confirmed by Annexin V/PI assay and histopathological examination. This was mediated by increased Bax expression, caspase-3 activation, decreased Bcl-2 expression, and MMP disruption. Furthermore, MCM treatment induced G1 cell cycle arrest which was mediated through significantly increased expression of p53, p21, and p27 and decreased expression of Cyclin D1 and PCNA in cancer cells. Finally, MCM treatment markedly enhanced NK cell cytotoxicity. Conclusion: MCM possesses chemopreventive potential to reduce tumor growth by suppressing cell proliferation, inducing apoptosis in EAC cells via a mitochondrial dependent pathway, and activating the immune system. Our results suggest that MCM may have clinical implications for the treatment of breast adenocarcinoma in humans. MCM was provided by the Foundation for Basic Research Institute of Oncology, Japan. Citation Format: Nariman K. Badr El-Din, Mai Alaa El-Dein, Mamdooh Ghoneum. Antineoplastic effect of marina crystal minerals (MCM) against the growth of murine mammary adenocarcinoma cells in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 691.
P1327: RUXOLITINIB COMBINED WITH GLUCOCORTICOID IN THE FIRST-LINE TREATMENT OF GRAFT-VERSUS-HOST DISEASE IN CHILDREN: A SINGLE CENTER RETROSPECTIVE STUDY
Authors: K. Chen, B. Zou, J.-B. Shao, Q. Liu, N. Zhang, P. Fu, X.-H. Sun, H. Jiang
Journal: HemaSphere (2022)

Background: Ruxolitinib has certain advantages and potential in the treatment of GVHD. It can inhibit the secretion of inflammatory factors by T cells, increase the number of regulatory T cells（Tregs）in the recipient, and then mediate immune tolerance. It can also reduce T cell surface related chemokines or chemokine receptors, and then change T cell migration. A multicenter retrospective study showed that the effective rate of ruxolitinib on glucocorticoid resistant aGVHD was 81.5%, and the effective rate of glucocorticoid resistant cGVHD was 85.4%. At present, there is no report on the first-line treatment of GVHD in children with glucocorticoid combined with glucocorticoid.Our center tried to use this combined scheme as the first-line treatment option in the early stage, in order to reduce the application time of glucocorticoid and reduce glucocorticoid related complications. Aims: To investigate the efficacy and safety of ruxolitinib combined with glucocorticoid in the treatment of graft-versus-host disease (GVHD) in children. Methods: A retrospective analysis of 17 cases of graft-versus-host disease（GVHD） after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in our center was conducted. The clinical efficacy and adverse reactions of early application of ruxolitinib combined with glucocorticoid were observed. Results: The median treatment time of 17 children was 47 (24-380) days, and the median onset time was 7 (4-90) days. The overall effective rate was 94.1% (16/17), the complete remission rate was 58.8% (10/17), the partial remission rate was 35.3% (6/17). The incidence of hemocytopenia during the combination therapy was 41.1% (7 /17).The incidence of EBV infection was 35.2% (6 /17), and the incidence infection of CMV was 29.4% (5/17).The incidence of hemorrhagic cystitis was 11.8% (2/17). The median follow-up time was 230 (74-545) days. One child died of grade IV acute graft versus host disease (aGVHD), and the other 16 children survived. The 6-month overall survival rate was 94.1%. Summary/Conclusion: Ruxolitinib combined with corticosteroid is effective and safe in the treatment of children with GVHD. It is expected to become a first-line anti GVHD therapy.
Optimization of Cas9 RNA sequence to reduce its unexpected effects as a microRNA sponge
Authors: Junfeng Jiang, Tao Zeng, Li Zhang, Xingfei Fan, Qishu Jin, Haitao Ni, Yusheng Ye, Lipeng Cheng, Li Li, Liujun Wang, Sha Xu, Yu Yang, Juan Gu, Bing Guo, Lei Wang, Xin Li, Yingyi Qin, Jiaxi Li, Jinjiang Wang, Xi Chen, Minjuan Wu, Qi-long Ying, Xingjun Qin, Yefei Wang, Yue Wang
Journal: Molecular Cancer (2022)

Cas9 RNA functions as a miRNA sponge. Let-7 is the dominant regulated miRNA by Cas9 RNA. RNA sequence optimization of Cas9 by synonymous mutation improves its safety.
PB2289: TRENDS IN ANTIGEN-NEGATIVE RED BLOOD CELL DISTRIBUTIONS ABOUT TEN THOUSAND THREE HUNDRED WHOLE BLOOD DONATIONS
Authors: F. Talbi, D. Djamel, D. djameli
Journal: HemaSphere (2022)

Background: The overall number of red blood cell (RBC) units distributed to hospitals throughout the world has significantly decreased lately. Aims: The aim of this study is to determine the prevalence of rhesus D negative in the population of whole blood donors in a region of central AlgiersWe carried out a retrospective study over a period of 10 years (2008-2017) including blood donors listed at the Boufarik PTS. We looked for a significant association of the D phenotype with the following variables: sex, age group and blood group. Methods: We carried out a retrospective study over a period of 10 years (2008-2017) including blood donors listed at the Boufarik PTS. We looked for a significant association of the D phenotype with the following variables: sex, age group and blood group. An antigen-negative unit was defined as a unit with a specific RBC phenotype that had been specially ordered as such by a hospital. Results: Out of n=10,300 blood donations, n=210 bags (NP grouping, carried out at the level of the reception structure), the median age is 23 ±5.19 years, group O represents 41%, group A: 35 %, group B=16% and group AB:05%. n=1129 RHD negative (11%), p<.000 (s): the distribution by sex (féminin = female, Masculin = Male) finds a non-significant threshold with the RHD neg: p=.25 (fig 1) and age: p=. 45 (fig 2) contrary to blood group: p<.000 (s) (fig 3) Image:Summary/Conclusion: The present study reveals that the negative RHD represents a non-negligible sample (11%) with a significant association with certain blood groups (p<.000) and emphasizes the potential risk of alloimmunization since the methods Current blood typing tests do not identify “variant” RhD phenotypes.
Abstract 6275: Evaluation of FRα/TRPV6 expression in gynecological cancer
Authors: Ning Li, Yifan Li, Wei Tan, Yan Teng, Baohua Huang, Lingying Wu
Journal: Cancer Research (2022)

Abstract Purpose:Folate Receptor Alpha (FRα) is highly expressed in multiple malignancies, including ovarian, NSCLC and breast cancer. Transient Receptor Potential Vanilloid 6(TRPV6) is upregulated in breast, ovarian and prostate cancer. However, there is no report on expression and correlation between expression of the two markers. Since both markers are highly expressed in ovarian cancer, it is of great interest to evaluate expression of FRα and TRPV6 in a panel of gynecological cancer, including those major subtypes. Method:We have collected 200+ FFPE samples achieved in pathology core at National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, including high grade and low grade serous ovarian cancer and clear cell ovarian cancer et al. Using validated IHC assays, expression of both FRα and TRPV6 are evaluated. Result:Various levels of FRα and TRPV6 express in different histological subtypes of ovarian cancer. High grade serous ovarian cancer expresses the highest levels of FOLR1, which is about 2.8 and 2 folds over that of low-grade ovarian cancer and that of clear cancer ovarian cancer, respectively. The highest levels of TRPV6 expression are observed in clear cell ovarian cancer, which is 2.6 and 1.6 folds over that observed in low grade ovarian cancer and that observed in high grade ovarian cancer, respectively. The two biomarker expression is overlapped in about 45% of all samples analyzed. A comparison of samples from patients with or without good response to neoadjuvant therapy reveals samples with poor responses tend to express higher levels of FRα than those with good responses do. Addition evaluation and analysis are still on-going. Conclusion: FRα and TRPV6 are highly express in gynecological cancer. Evaluation of their expression is of great value for molecularly-targeted therapies for those two targets and provide a precision medicine option for the clinical development for such drugs. Citation Format: Ning Li, Yifan Li, Wei Tan, Yan Teng, Baohua Huang, Lingying Wu. Evaluation of FRα/TRPV6 expression in gynecological cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6275.
P1665: WHOLE-BLOOD ROTATIONAL THROMBOELASTOMETRY (ROTEM) AS A DIAGNOSTIC TOOL IN PATIENTS WITH BLEEDING OF UNKNOWN CAUSE (BUC)
Authors: D. Mehic, B. Jilma, C. Schörgenhofer, M. Colling, C. Ay, I. Pabinger, J. Gebhart
Journal: HemaSphere (2022)

Background: A majority of patients with a mild to moderate bleeding tendency (mild bleeding disorders, MBD) remains without a diagnosis, despite extensive laboratory investigations (bleeding of unknown cause, BUC). Patients with BUC do not differ in their bleeding phenotype to patients with an established MBD like von Willebrand disease (VWD) or platelet function defects (PFD). Whole-blood thromboelastometry (ROTEM) depicts diverse aspects of coagulation including hyper-fibrinolysis and captures the influence of erythrocytes, leucocytes and platelets to hemostasis, which might contribute to BUC. Aims: To analyze clinical risk factors for ROTEM parameters and compare results between patients with BUC and an established MBD. Methods: Patients from the Vienna bleeding biobank (VIBB, EC no. 603/2009) were analyzed (Gebhart et al, Haemophilia, 2018). Viscoelastic clot measurement was performed with non-activated ROTEM® (EM International, Munich, Germany): clotting time (CT, sec, time from analysis start until start of clot formation), clot formation time (CFT, sec, time needed to form a clot), maximum clot firmness (MCF, mm, peak amplitude of the clot) and maximal lysis (ML, %, expression of clot lysis in % of MCF). Results: ROTEM was performed in 513/714 (71.8%) patients included in the VIBB. The mean(SD) age was 41.4 (15.0) years, 425 (80.3%) were women and 252 (47.6%) patients had blood group O. In total, 318 patients had BUC, the reaiming patients hat PFD(n=122, 23.7%), VWD (n=51, 9.9%), mild clotting factor deficiencies (CFD, n=18, 3.5%) and 4 had an other bleeding disorder (0.8%). Clinical factors that were independently associated with ROTEM values in BUC patients were sex, blood group O (vs. non-O) and the bleeding score (multivariable linear regression, Table 1). BUC patients had comparable ROTEM results as patients with platelet function defects or VWD, after adjusting for blood group O and sex, whereas patients with clotting factor deficiency had longer CT and CFT, a lower MCF and higher ML (Table 2). Image:Summary/Conclusion: Hemostatic capacity measured by ROTEM is similar in patients with BUC and those with mild primary hemostatic bleeding disorders. Our data support the hemostatic imbalance in patients with BUC.
P967: TUMOR BURDEN AS A CRITICAL PROGNOSTIC FACTOR OF PRIMARY EXTRAMEDULLARY DISEASE
Authors: M. Vlachová, M. Štork, S. Ševčíková, T. Jelínek, J. Minařík, J. Radocha, P. Krhovská, L. Pospíšilová, I. Špička, J. Straub, P. Pavlíček, A. Jungová, V. Sandecká, V. Maisnar, R. Hájek, L. Pour
Journal: HemaSphere (2022)

Background: Multiple myeloma (MM) is the second most common hematological malignancy characterized by malignant plasma cell (PC) infiltration of the bone marrow (BM). In the case of extramedullary MM (EMD), plasma cells survive and proliferate outside of the bone marrow microenvironment. Primary EMD is found in newly diagnosed MM (NDMM) patients. Aims: The aim of this study was to describe clinical features and treatment outcomes of primary EMD patients and to define possible risk factors. Methods: In total, 724 primary EMD patients were diagnosed in the Czech Republic between 2004 and 2021 by using modern imaging methods. As a reference group, 2440 MM patients without any evidence of EMD were used. All patients enrolled into the analysis were treated by novel agents. Patients’ data were analyzed from the Registry of Monoclonal Gammopathies of the Czech Myeloma Group (RMG). Results: Primary EMD patients had less frequently advanced ISS (ISS 3) (OR 0.51 [95% CI: 0.42–0.63], p<0.001), high paraprotein levels (>20g/l) (OR 0.64 [95% CI: 0.54–0.76], p<0.001) and high PC infiltration of bone marrow (>10%) (OR 0.35 [95% CI: 0.30–0.42], p<0.001) when compared to reference MM patients. Median PFS in newly diagnosed primary EMD patients was comparable to reference MM patients (23.2 months [95% CI: 21.2–26.2] vs. 23.3 months [95% CI: 22.5–24.8], p=0.800). Median OS was comparable to reference patients (52.6 months [95% CI: 46.3–62.0] vs. 55.0 months [95% CI: 51.6–58.9], p=0.504). By multivariate analysis, adjusted for ISS, we found high levels of BM PCs (>10%) together with 3 and more EMD lesions as an independent risk factor for inferior survival in primary EMD patients (PFS: HR 1.92 [95 % CI: 1.28–2.87]; OS: HR 2.06 [95 % CI: 1.35–3.14], both p=0.001). Summary/Conclusion: We found primary EMD patients distinct from reference MM patients. Survival intervals of both groups of patients were comparable. We found that the intra- and extramedullary tumor burden is an independent key factor influencing primary EMD prognosis. This work was supported by grant AZV NU21-03-00076.
The United States needs people to stand up for abortion
Authors: Sharon Lau
Journal: BMJ (2022)

<h3>Background</h3> Adoptive immunotherapy using chimeric antigen receptor (CAR) is recently reported as one of the effective cancer therapy. Especially CAR-T cell therapy targeting CD19 antigen in B-cell tumors have shown impressive clinical results and CAR-T cell products targeting CD19 have already approved. However as the high relapse rate is still the problem and the clinical efficacy of CAR-T cell therapy for solid tumors is currently inadequate, further improvement of CAR design is required.It is known that the design of CAR construct affects the function of CAR-T cells. For example co-stimulatory domain such as CD28 and 4-1BB is used in the second generation CARs, CD28z-CAR-T cells show higher anti-tumor activity, whereas 4-1BBz-CAR-T cells demonstrate superior in vivo persistence. To enhance survival of T cells, several attempts had been made to optimize the signaling domains. Recently, we have developed the novel CARs incorporated GITR (glucocorticoid-induced tumor necrosis factor receptor family-related protein) intracellular domain for T cell survival prolongation and inhibition of regulatory T cells’ suppressive activity. It is also reported that the antigen-nonspecific activation of CAR-T cells (tonic signaling) is influenced by the CAR design, and excessive T cell activation leads exhaustion of CAR-T cells. Previously, we have found that the design of CAR, not only single chain variable fragments (scFvs), affect the strength of tonic signaling. Thus, the optimization of CAR construct is essential to induce antigen-specific response with minimal non-specific activation, which results in maximal efficacy. <h3>Methods</h3> We have optimized the structure of anti-CEA-GITR-CAR targeting CEA antigen expressing solid tumor such as gastric and pancreatic cancer. We have constructed several CARs with the different composition such as hinge region, transmembrane domain, and the order of VL/VH in scFV region, and compared the tonic signaling and antigen-specific activity in CAR-T cells. <h3>Results</h3> The property of CAR-T cells was largely affected by the CAR constructs, especially the hinge region. The CAR-T cells with CD8α hinge showed strong tonic signaling, the CAR-T cells with short hinge-CAR lost antigen specificity, and elimination of hinge region lowered the CAR expression level and antigen reactivity. Furthermore, GITR-CAR-T cells showed higher proportion of CCR7+CD45RA+ cells and lower expression of exhaustion markers (PD1, Tim3, and LAG3) compared to CD28z-CAR-T cells. <h3>Conclusions</h3> Our CEA-GITR-CAR with the optimized scFV design and CD28-hinge demonstrated improved antigen-specific response with reduced tonic signaling, potentially indicating that our novel CAR-T cells may show improved clinical efficacy on solid tumor.
PB2157: TREATMENT WITH DIPHENYLENEIODONIUM CHLORIDE EXHIBITS CELL GROWTH INHIBITORY EFFECTS ON AGGRESSIVE LYMPHOMA CELLS
Authors: S. Haingartner, S. Jantscher, K. Pansy, M. Szmyra, P. Neumeister, H. Greinix, A. Deutsch
Journal: HemaSphere (2022)

Background: Non-Hodgkin lymphoma (NHL) represent the most common hematologic malignancies in the world. Especially the incidence of diffuse large B-cell lymphoma (DLBCL) as one aggressive subtype increases and up to 40% of patients relapse or do not attain complete remission. Thus, there is an urgent need to develop new drugs and employing them in novel therapeutic strategies. Transcription profiling identified a DLBCL subgroup that exhibits increased expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) and which is insensitive to B-cell receptor inhibition. Aims: Therefore, the aim was to investigate whether OXPHOS inhibition could be therapeutically targeted. Methods: Six different lymphoma cell lines (Karpas422 and SuDHL4 as germinal center B-cell-like (GCB) DLBCL models, RI-1 and U2932 as activated B-cell-like (ABC) DLBCL models, BL2 as Burkitt lymphoma model and Jurkat as model for T-cell NHL) were used and cultured with Diphenyleneiodonium chloride (DPI) – an OXPHOS inhibitor. To analyse the in vitro effects of DPI cell-growth assays as well as cell-cycle analysis and apoptosis assays were performed. Results: After 72 hours of DPI exposure, a concentration-dependent growth inhibition in all investigated cell lines was detected by MTS assay. Especially, DLBCL cell lines exhibited low IC50 values ranging from 12nM to 40nM, whereas IC50 values for BL2 (149nM) and Jurkat (640nM) cells were higher (p=0.071). Furthermore, DPI treatment (250nM, 50nM and 10nM) of SuDHL4 and BL2 cells induced a cell cycle arrest in the S phase in comparison to untreated cells after 24 hours. In Jurkat and U2932 cells, a change in cell cycle distribution was also observed but to a lower extend. Interestingly, in none of these four cell lines (SuDHL4, BL2, Jurkat and U2932) apoptotic effects were detected. Summary/Conclusion: These preclinical data indicate that DPI treatment causes cell growth inhibition, which is mediated by changes in cell cycle distribution. Thus, pharmacologic inhibition of OXPHOS might serve as a novel therapeutic approach for further DLBCL therapies and the mechanism behind it should be deciphered in more detail.
Abstract SY41-03: Cancer specific amino acid metabolism
Authors: Oliver Maddocks
Journal: Cancer Research (2022)

Abstract The growth &amp; proliferation of cancer cells is fundamentally dependent on metabolic processes, and tumours frequently display altered metabolism compared with healthy tissues. To sustain enhanced growth, and to resist stresses associated with cancer treatments, cancer cells become highly dependent on the uptake of exogenous nutrients, particularly amino acids. Amino acid metabolism supports tumour growth and survival in numerous ways, particularly in the provision of anabolic precursors for macromolecule (e.g. protein and DNA) synthesis, as well as stress responsive antioxidant pathways (e.g. glutathione/GSH synthesis). We have shown that uptake of exogenous serine and glycine is key nutrient dependency for many cancer cells, simultaneously supporting THF-dependent one carbon metabolism and GSH synthesis. More recently we have defined a role for immune-regulated IDO1 dependent tryptophan metabolism as an alternative one-carbon source for nucleotide synthesis, underlining the potential flexibility of tumour metabolism. The sensitivity of certain cancer cells to cysteine starvation is well established, and multiple mechanisms contribute to cysteine withdrawal sensitivity, including transsulfuration activity and methylation reactions. We have recently defined a role for methionine driven polyamine metabolism in sensitising cells to cysteine starvation, particularly in the context of MTAP gene deletion. Improved understanding of cancer specific amino acid metabolism is defining genetically driven metabolic vulnerabilities that can be therapeutically exploited by a combination of diet and small molecules. Citation Format: Oliver Maddocks. Cancer specific amino acid metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY41-03.